New camphor derivatives and the method of preparing them



3,007,926 NEW CAMPHGR DERIVATIVES AND THE METHOD OF PREPARING THEMMichio Nakanishi, 1421 3-Cl1ome, Tonomachi,

Nakatsu-shi, Ooita, Japan N Drawing. Filed Sept. 12, 1958, Ser. No.760,567

Claims priority, application Japan Sept. 18, 1957 1 Claim. (Cl.260-2471) The present invention relates to new camphor derivatives andto a process for preparing the same.

More particularly the invention relates to the new compound of thegeneral formula o o o-a-nm X Y Rs wherein X is selected from the groupconsisting of halogen atoms, hydroxyl radical and hydrogen atom; A isselected from the alkylene groups with 2-5 carbon atoms; R and R areeach selected from the group consisting of hydrogen atom, lower alkylradicals and, by the two, bi valent groups forming rings with thenitrogen atom present in the Formula (I); R is selected from the groupconsisting of alkyl radicals and ara'lkyl radicals; Y is selected fromthe group consisting of halogen atoms, arylsulfonyloxy groups andalkylsulfate groups;

The lower alkyl radicals, which are designated by R and R in the generalFormula (I) mentioned above, indicate the radicals such as, for example,methyl, ethyl, propyl and so forth, and the ring with two-valencies inwhich nitrogen atom is involved corresponds to such radicals as, forinstance, piperidino, morpholino, piperazino, pyrrolidino etc.

The camphor derivative of the general Formula (I) can be produced fromthe camphor derivative of the general formula wherein each of X, A, Rand R is the same as that mentioned above;

by reaction with a compound of the general formula R Y wherein each of Rand Y is the same as that mentioned above.

The reaction may be conducted preferably in organic solvents such asbenzene, toluene, and alcohol, which are inert with respect to thereactions. The reaction generally takes place even at room temperature,but more effectively under heating.

Supremacy of this chemical compound obtainable by the method under thisinvention in eificiency of reducing blood pressure, though being novelchemical compound unrevealed yet in any literature, can be recognizedfrom the hereunder mentioned examination.

By the use of N-methyl-N-(2-isoketopinoyl-oxyethyl)- morpholinium iodideto be obtained by Example 4 as sample medicine as hereunder mentioned,the following result can be given by such experimental method as statedlater.

tates Patent 0 M 3,007,926 Patented Nov. 7, 1961 By giving 0.1 mg./kg.of this chemical compound to an adult dog, hypotensive effect wasalready recognized and by 0.25 mg./kg., longlasting remarkablehypotensive efiect was resulted. The ultimate lowering degree by giving0.5 mg./ kg. is approximately 50 mm. Hg, and duration thereof was about20 minutes.

In the above experiment a pentobarbital anesthetized dog.( approximately10 kg. weight) was used for experimental animal and blood pressure ofcarotid artery and coxa artery was recorded with the aid of mercurymanometer, and the test compound was injected into vein of a leg of thedog under test.

The camphor derivatives shown above, which are employed as raw materialin the preparation of this invention, have a general formula,

(III) where each of X, A, R and R is similar as previously employed.This is also a new material and can be prepared from the reactionbetween camphor derivatives, of which general formula is OOOH (IV)wherein X is the same as that mentioned above; or their reactivecarbonic acid derivatives (such as, for example, alkali or alkali earthmetal salts of carbonic acid, or carbonic acid ha'logenides of chlorineor bromine, or carbonic acid alkyl or aryl esters) and aminoalkanole, ofwhich general formula is N-A0H R2 (V) wherein each of R and R is thesame as mentioned above; or its reactive derivatives (such as, forexample, its halogenides or esters such as sulfuric acid ester ororganic sulfonic acid ester).

Many combinations are possible for the reaction between the camphorderivatives (IV) (or its reactive carbonic acid derivatives) andaminoalkanole (V) (or its reactive derivatives), and in each case itsreaction conditions, such as decarboxyl agent, condensation agent,reaction solvent, or reaction temperature, can suitably be employedreferring to the experimental conditions in the general es-terificationreaction.

The method of the present invention is explained by example as follows:

Example 1 To a solution of 14 g. of Z-diethylaminoethyl isoketopinateX:H, R1=R2:C2H5) in cc. of benzene 8 g. of ethyl iodide (R =C H Y=I) isadded and the mixture is heated for 10 hours. The precipitatedcrystalline substance is collected by filtration and recrystallized froma mixture of acetone and ethyl acetate to givetriethy1-(2-isoketopinoyloxyethyl)-am 3 monium iodide (I, X=H, A=CH CH R=R =R =C H Y=I) melting at 152 C.

Example 2 To a solution of g. of Z-dimethylaminoethyl isoketopinate (II,X=H, A=CH CH R =R =CH in 100 cc. of benzene 6 g. of methyl iodide (R =CHY=I) is added with cooling. The mixture is heated for 5 hours. Thereaction gives trimethyl-(2isoketopinoyloxyethyl)ammonium iodide (I,X=H, A=-CH CH R =R =R =CH Y=I) melting at 208 C.

Example 3 Fifteen grams of 3-dimethylaminopropyl isoketopinate (II, X=H,A=-CH CH CH R =R =CH and 8 g. of methyl iodide (R =CH Y=I) in 100 cc. ofhenzene, treated as Example 2, givetrimethyl-(3-is0ketopinoyloxypropyl)ammonium iodide (I, X=H,

A=CH2CH2CH2 R =R =R =CH Y=I) melting at 181 C.

Example 4 Ten grams of 2-morpholinoethyl isoketopinate (II, X=H, A=CH CHR R :CH CH OCH CH and 5 g. of methyl iodide (R =CH Y=I) in 100 cc. ofbenzene, treated as Example 2, giveN-methyl-N-(Z-isoketopinoyloxyethyl)morpholinium iodide (I, X=H,

A=CH CH R R =CH CH OCH CH R =CH Y=I) melting at 231 C.

Example 5 Twenty-three grams of 2-piperidinoethyl isoketopinate (II,X=H, A=CH CH R1R2 and 11.5 g. of methyl iodide (R =CH Y=I) in 100 cc. ofbenzene, treated as Example 1, give N-methyl-N-(Z-isoketopinoyloxyethyl)piperidinium iodide (I, X=A,

A:CH2CH2, R1R2:-CH2CH2CH2CH2CH2.

R =CH Y=I) melting at 208 C.

Example 6 Five grams of 3-m0rpho1inopropy1 isoketopinate (II, X=H, A=CHCH CH R R =CH CH OCH CH and 2.3 g. of methyl iodide (R =CH Y=I) in 50cc. of benzene, treated as Example 1, give N-methyl-N-(3-isoketopinoyloxypropyl)morpholinium iodide (I, X=H,

A=CH CH CH R R =-CH CH OCH CH R=CH Y=I) melting at 205 C.

Example 7 Six grams of 3-piperidinopropyl isoketopinate (II,

X=H, A=-CH CH CH R1R2:CH2CH2CH2CH2CH2-) and g. of iodide (R =CH Y=I) in50 cc. of benzene, treated as Example 1, giveN-methyl-N-(3-isoketopinoyloxypropyl)- piperidinum iodide (I, X=H, A=CHCH CH R R =CH CH CH CH CH R =CH melting at 190 C.

Example 8 Thirteen grams of 2-morpholinoethyl isoketopinate (II, X=H,A=CH CH R1R2=CH2CH2OCH2CH2) and 5.8 g. of propargyl bromide (R =CHECCHY=Br) 50 cc. of benzene, treated as Example 1, give Five and a halfgrams of 2-morpholinoethyl-a-chloroisoketopinate (II, X=Cl, A=-CH CH and2.8 g. of methyl iodide (R =CH Y=I) in 50 cc. of benzene, treated asExample 1, give N-methyl-N-(Z-achloroisoketopinoyloxyethyl)morpholiniumiodide (I, X=Cl, A=CH CH R R =-CH CH OCH CH R =CH Y=I) melting at 219 C.

Example 11 Nine grams of N,N' bis (2 isoketopinoyloxyethyl)- piperazine(VI) C Hz C a K and 3.1 g. of methyl iodide (R =CH Y=I) in benzene,treated as Example 1, give N-methyl-N,N-bis-(2-isoketopinoyloxyethyl)piperazinium iodide (VII) melting at 197 C.

(VII) Example 12 Nine grams N,N'-bis-(2-isoketopinoyloxyethyl)piperazine(VI) and 6 g. of methyl iodide (R =CH Y=I) in 500 cc. of alcohol areheated under pressure on a waterbath for 15 hours. Bis-methiodide (VIII)melting at 220 C. is obtained.

l/omogz /CH3 (W -COOCHzCHzN N--CH2CHzOOC- t) I 01120112 I (VIII) Example13 Eleven grams of 4-m0rpholino-2-butyny1 isoketopinate (II, X=H,A=CH2CECCH2-,

and 10 g. of methyl iodide (R =CH Y=I) in cc. of benzene are heated for7 hours. The oily product is dissolved in alcohol. The oil precipitatedby adding ether to the alcoholic solution is dried to give N-methyl-N-(4-isoketopinoyloxy 2 butynyl)morpholinium iodide (I, X:H, A=CH CECCHR R =-CH CH OCH CH R =CH Y=I) in extremely hygroscopic powder melting at85 C.

Example 14 Eleven grams of 4-morpholinobutyl isoketopinate (II, X=H,A=CH CH CH CH is treated in the same way as Example 13. N-methyl- N (4isoketopinoyloxybutyl)morpholinium iodide (I, X=H, A=CH CI I CH CH R =CHY=I) is obtained as an extremely hygroscopic substance melting at 65 C.

The preparation of some starting materials in this invention isdescribed in the case of a few examples as follows:

(1) 40 g. of isoketopinic acid chloride and 27 g. of2-oxyethyl-morpholin are heated in xylene. After cooling the solution,xylene layer is washed with aqueous solution of sodium carbonate andthen extracted with dilute hydrochloric acid. Sodium hydroxide is addedin the acid solution until it becomes a strong alkaline solution. Thus2-morpholin0ethyl isoketopinate can be obwherein X is selected from thegroup consisting of halogen, hydroxyl and hydrogen; A is alkylene of 2to 5 carbon atoms; R and R are each selected from the group consistingof lower alkyl of 1 to 3 carbon atoms and groups forming together withthe N-atom a member selected from the group consisting of piperidino,morpholino, piperazino and pyrrolidino; R is selected from the groupconsisting of lower alkyl of 1 to 3 carbon atoms and propargyl, and Y ishalogen.

References Cited in the file of this patent UNITED STATES PATENTS2,797,227 Jenkins June 25, 1957

